Peptide, polypeptide and protein-based compounds used in medicine as antiviral drugs are known. Among type I interferon inducers (IFI) they are known as high-molecular compounds [F. I. Yershov, O. I. Koselev. Interferons and their inducers from the molecule to the drug —, M.: Publ. House. Geotar—Media, 2005-P. 356], [Berg K., Bolt G., Andersen H., Owen T C. Zink potentiates the antiviral action of human IFN-alpha tenfold. J. Interferon Cytokine Res, 2001, July; 21(7):471-4], as low-molecular inducers. From the latter, first of all, native drug cycloferon and American drug imiquimod should be noted. These drugs refer to acridone and benzimidazole derivatives, respectively. For imiquimod and close derivatives, Toll-like type of receptors is known, with which this group of drugs interacts causing IFN-α synthesis induction in various cells [F. I. Yershov., O. I. Kiselev. Interferons and their inducers (from the molecule to the drug) M.: Publ. House. Geotar—Media, 2005.-P. 356].
Bioactivity of low-molecular peptides is widely known. First of all, this refers to animal and plant origin peptides with antibacterial activity [Boman H. Peptide antibiotics and their role in innate immunity. Anu. Rev. of Immunol., 1995, Vol. 13, p. 61-92]. However, a number of peptides possessing direct antiviral and antitumour action has been described [Akiyama N., Hijikata M., Kobayashi A., Yamori T., Tsuruo T., Natori S. Anti-tumor effect of N-β-alanyl-5-S-glutathionyl dihydroxyphenylalanine (5-S-GAD) a novel anti-bacterial substance from an insect. Anticancer Research, 2000, Vol. 20, p. 357-362].
Peptides of amphibians and insects take a special place here [Bulet P., Hetru C., Diamarcq J., Hoffmann D. Antimicrobial peptides in insects: structure and function. Devel. Comp. Immunol., 1999, Vol. 23, p. 329-344, Chinchar V. G., Wang J., Murti G., Carey C., Rolling-Smith L. Inactivation of frog virus 3 and channel catfish virus by esculentin-2P and ranatuerin-2P, two antimicrobial peptides isolated from frog skin. Virology, 2001, Vol. 288, p. 351-357].
Immunomodulating peptides—alloferons are known (patent of the RF No. 2172322). Treatment of viral infections is the main area of application for alloferons. Alloferons are the closest analogues of the present invention regarding chemical structure and mode of action.
It should be noted, that inventors of the U.S. Pat. No. 2,172,322 only consider variations of primary alloferon structure and do not place key value to histidine residues distribution.
Moreover, alloferons should be referred to quite “weak” interferon inducers, which is evident when comparing their activity with cycloferon.
At the same time, alloferons structure stands out with regular histidine residues arrangement and frequent glycine residues. Enhancement of alloferons structure is possible towards giving them tertiary structure elements, for instance, by introduction of metal ions.
Hemin-peptide and its pharmaceutically acceptable salts with virucidal and antiviral action, containing metal ions, where Zn, Cu, Fe, Mn can be used, is also known. (patent of the RF 2296131). However, this compound refers to the second class of peptides and is not an immune modulator.
Peptide complexes with Zn++ ion, with elements of organized tertiary structure and activity of first type interferon inducers, are not described in the literature.
Need for modification of histidine-containing peptides with Zn++ ion is driven by the following causes:
1. Bioactive short peptides have disorganized type of secondary structure inevitably reducing their bioactivity, interactability with other macromolecules, metabolic stability.
2. Biological and pharmacological activity of peptides largely depends on transport efficiency to cells. Making peptide structure compact increases effectiveness of their translocation through membranes and, subsequently, pharmacological activity [Leng Q., Mixson J. Modified branched peptides with histidine-rich tail enhance in vitro gene transfection. Nucl. Acids. Res., 2005, Vol. 33, e40].
3. Formation of histidine-containing peptide complexes with Zn++ ion results in fundamental changes of peptides properties, making them identical with domains of transcriptional activators of viruses and cells.